Continuous double layered stent for migration resistance

ABSTRACT

The present invention relates to stent structures having improved migration resistance. In particular, the invention relates to mesh stents, such as braided or twisted stent designs, where at least a portion of the stent is folded back over itself to form a multi-layered stent device. Such multi-layered portions provide for migration resistance, among other advantages.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention is a continuation of U.S. patent application Ser.No. 12/483,488, filed on Jun. 12, 2009, is a non-provisional conversionof U.S. Patent Application Ser. No. 61/061,800, filed on Jun. 16, 2008,the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to stent structures having improvedmigration resistance. In particular, the invention relates to meshstents, such as braided stent designs, where at least a portion of thestent is folded back over itself to form a dual-layered stent device.Such dual-layered portions provide for migration resistance, among otheradvantages.

BACKGROUND OF THE INVENTION

An intraluminary prosthesis, for example a stent, is a medical deviceused in the treatment of diseased bodily lumens. A stent is generally alongitudinal tubular device formed of biocompatible material which isuseful to open and support various lumens in the body. For example,stents may be used in the bodily vessel, such as in the coronary orperipheral vasculature, esophagus, trachea, bronchi colon, biliarytract, urinary tract, prostate, brain, as well as in a variety of otherapplications in the body.

A stent generally includes an open flexible configuration which allowsthe stent to be configured in a radially compressed state forintraluminary catheter implantation. Once properly positioned adjacentthe target body lumen, the stent is radially expanded so as to supportand reinforce the vessel. Radial expansion of the stent may beaccomplished by inflation of a balloon attached to the catheter or thestent may be of the self-expanding variety which will radially expandonce deployed. Balloon expandable and self-expanding stents are known.Such self-expandable stents in use include those in the Applicant'sWallFlex® stent family, including the WallFlex® Enteral, Esophageal andBiliary stent designs.

To prevent migration of the stent after implantation, the stent isanchored to the inner wall of the lumen. On occasion, however, it may benecessary after implantation to remove a stent that is anchored to thebody lumen or to shift the placement of the stent after implantation.However, in current stent devices, due to the anchoring of the stent tothe inside wall of the body lumen, such removal or shifting may bedifficult, if not impossible.

Thus, there is a need for a stent or intraluminal prosthesis whichprovides improved migration resistance, as well as allowing for easy invivo adjustment and/or removal of the stent. The present invention meetsthese needs and provides advantages beyond those known in the art.

SUMMARY OF THE INVENTION

The present invention incorporates a continuous dual-layered stentdevice, which allows for sufficient anchoring while reducing the risk ofmigration, and additionally allows for shifting and/or removal of thestent after implantation.

In another embodiment of the invention, there is provided a stentincluding a stent body, which has a cylindrical mesh segment, thecylindrical mesh segment formed from at least one wire, where the wireforms a plurality of intersecting crossing points to define an openlattice tubular wall; and at least a portion of the open lattice tubularwall is inverted upon itself to form a dual layered cylindrical meshsegment. Desirably the plurality of intersecting points from a braid orbraided section(s). Desirably the stent is made from 8 to 24 wires.

In one embodiment of the invention, there is provided a generallytubular stent, which includes: an inner braided section and a concentricouter braided section, where the outer braided section forms acontinuous braid with the inner braided section. Both the inner andouter braided section includes at least one wire, which has intersectingcrossing points to define the braided section.

In another embodiment, there is provided a method of implanting atubular stent including the steps of: implanting a stent, wherein thestent comprises: a first stent body having a generally cylindrical meshsegment, the mesh segment formed from at least one first wire, and thefirst wire forming a plurality of intersecting crossing points to definean open lattice tubular wall; and implanting a second stent, wherein thestent includes: a second stent body having a generally cylindrical meshsegment, the mesh segment formed from at least one second wire, and thesecond wire forming a plurality of intersecting crossing points todefine an open lattice tubular wall; and at least partially connectingan end of the first stent body to an end of the second stent body toform a multi-layered stent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an embodiment of the present invention showing thedouble braided stent device.

FIG. 2A is an exploded view of a stent of the present inventionillustrating a one-under and one-over braiding configuration.

FIG. 2B is an exploded view of a stent of the present inventionillustrating a two-under and two-over braiding configuration.

FIG. 2C is an exploded view of a stent of the present inventionillustrating a pair of filaments in a one-under and one-over braidingconfiguration.

FIG. 3 illustrates an embodiment of the present invention, prior to theouter segment being folded over the inner segment.

FIG. 4 illustrates the embodiment of FIG. 3, after the outer segment hasbeen folded over the inner segment.

FIG. 5 illustrates an embodiment of the present invention incorporatinga twisted configuration of filaments.

DETAILED DESCRIPTION OF THE INVENTION

Devices having improved migration resistance, as well as otheradvantages, are provided. The devices and assemblies may be suited forvarious medical applications, and particularly, minimally invasive orintraluminal applications, in various bodily lumens, including but notlimited to the gastrointestinal tract, the biliary tract, the urinarytract, and the respiratory tract. Further, the assembly in accordancewith the present invention could also be used in the neurological system(e.g., in the brain) and in the cardiovascular system (e.g., in theheart). Reference to bodily passageways may be to passageways in any ofthe aforementioned tracts and systems or elsewhere in the body,including fabricated lumens or openings.

While the present invention may be applied to the delivery of manyintraluminary devices, it is particularly suited for stents, and moreparticularly of self-expanding stents. Such stents and delivery systemsfor the stents are generally known in the art. Those stents particularlyuseful in the present invention are capable of being radially compressedand longitudinally extended for implantation into the bodily lumen. Thedegree of elongation and the diameter of the stent may be quite varied,depending upon the desired lumen in which the stent is to be implanted.It is particularly desirable that the stent be constructed toself-expand when released from a radially compressed state, for exampleduring deployment.

With reference to FIG. 1, one embodiment of the stent device 10 of thepresent invention is provided. The stent 10 is a hollow, generallycylindrical mesh structure, having two axially opposite open ends 16 and22. The structure of the stent 10 includes a series of wires orfilaments 20, which preferably extend at least a majority of the lengthof the stent 10, and most preferably the entire length of the stent 10.

The filaments 20 are preferably elastic shape-memory alloy wires, forexample, those made from superelastic materials such as nitinol, andmost preferably the type which allow for self-expansion. Other materialsmay include shape memory polymers or metals, or simply elasticmaterials. Further, materials may also include plastically expandablematerials. The filaments 20 preferably form an open lattice tubularwall. In one preferred embodiment, the filaments 20 are continuouslywoven together in a braided form, as will be described in more detailbelow. The structure is not limited to woven structures, and includesother such fabrications as knitting, braiding, crocheting, welding,suturing, tying, or other such methods of producing interconnectedstructures. FIG. 5 depicts one such alternate structure, which uses atwisted structure. In a twisted structure, the filaments 20 are twistedaround each other at least one time. There may be multiple twists ateach twist location. FIG. 5 depicts a dual-twist structure, having twotwists 28 and 30 at each twist location.

In a preferred embodiment, the stent 10 includes at least two meshsegments, in particular an inner segment 12 and an outer segment 14. Thetwo segments 12 and 14 are preferably hollow, generally cylindricalbodies, and are formed of mesh filaments 20. The two segments 12 and 14may be different in structure, manufacture, size or design. For example,one may be braided, while another may be crocheted, or one segment mayhave layer cells, while the other does not. In addition, the twosegments 12 and 14 may be made from different materials or they may bemade from the same materials. The inner segment 12 and the outer segment14 are preferably disposed concentrically, with the outer segment 14being located on the outside surface of the inner segment 12. The twosegments 12 and 14 are desirably formed from the same continuouslyinterconnected mesh structure, and may be formed for example by forminga first segment of a stent body 10 and inverting one end of the stentbody 10 back upon itself to form a multi-layered, generally cylindricalmesh segment. In one embodiment, the mesh segment includes two layers.Of course, the two segments 12 and 14 may not be made from the samecontinuously interconnected structure, and may be attached by a frictionfit or other non-permanent fits. The outer segment 14 may cover theentire length of the inner segment 12, or it may cover only a portion ofthe inner segment 12. In an alternative embodiment, the outer section 14may extend beyond the length of the inner segment 12. There may be oneor more additional layers, such as other stents, coatings or liners,disposed between the inner segment 12 and the outer segment 14, or thesegments 12 and 14 may be disposed directly on each other. Either inner,outer, or both segments may be coated or covered, and may have the sameor varying mechanical properties. Use of a double layered stentconfiguration provides superior anti-migration abilities.

The use of the multiple layer design aids in anchoring the stent 10 tothe implant site, and further aids in the removal of the stent 10 if theneed arises. In addition, the use of the multi-layered design allows forrepositioning of the stent 10 even after it has been implanted. Themultiple layer design may also aid in self-sizing of the stent 10. Forexample, the stent 10 may include a self-sized area disposed between theinner and outer segments 12 and 14, so that the user may move the layerswith respect to each other but not the self sized area.

Braiding of the filaments 20 may be accomplished by any desired means.One such preferred braiding means is through the use of a braidingmandrel, although any desired braiding means may be used. For example,such stents 10 may be braided via the use of braiding mandrels havingspecifically designed grooves and detents and constant force braidingcarriers for tangentially delivering filaments 20 for braiding thefilaments 20 onto such specifically designed mandrels. The braidingangle throughout the stent 10 preferably is substantially constant,although there may be slight differences in the angle between the innersegment 12 and the outer segment 14. The braiding angle is preferablybetween about 90° to about 130°, and most preferably is between 100° to120°. Further, other regions, such as flared or tapered ends, may havedifferent angles than the rest of the stent 10. For example, in oneembodiment, the braiding angle may be about 110°±3°, desirably about110°±1°. In some embodiments, the present invention may avoidundesirable variations through the use of such components as, interalia, constant force carriers, constant force bobbin carriers, using abraiding mandrel having raised projections, and/orstent-filament-holding detents on the mandrel. In some embodiments, thebraiding angle may be varied throughout the length of the stent 10.

The braiding of the filaments 20 may be arranged in any number ofacceptable ways. Several suitable braiding configurations are depictedin FIGS. 2A-2C, which are exploded views 24 of the stent 10 of FIG. 1.For example, the braiding may be “one-under and one-over” style. Theone-under and one-over braiding configuration is depicted in an explodedview in FIG. 2A. In this embodiment, the braiding arrangement includesfilaments 20 which alternate in a braiding pattern having a 1/1intersection, i.e., one-under and one-over pattern. The stent 10,however, is not limited to any specific braiding pattern. As depicted bythe exploded view 24 in FIG. 2B, the braiding arrangement may includethe filaments 20 braided in a two-under and a two-over pattern. Further,as illustrated in FIG. 2C, the braiding arrangement may be accomplishedby using a pair of filaments 20′ in a one-under and one-over pattern.The pair of filaments 20′ may be the same or may be different, i.e., mayhave the same or different dimensions, shapes and/or materials ofconstruction. Moreover, the pair of filaments 20′ may suitably bebraided in other braided patterns, such as but not limited to, forexample, the two-under and two-over pattern described above. Otherbraiding patterns known in the art may also be suitably be used. Someportions of the mesh segments may be non-interlocking if desired,including such designs as inter-twisting, inter-looping, inter-engagingand the like at the intersection of the braided filaments 20, 20′. Otherbraiding patterns include those described in U.S. Pat. No. 5,800,519 toSandock, the contents of which are incorporated herein by reference.

In one embodiment, the inner segment 12 and the outer segment 14 areconnected together in one continuous piece, where the outer segment 14is inverted or folded over the inner segment 12. Thus, some of thefilaments 20 of the inner segment 12 are common to some of the filaments20 of the outer segment 14. In an alternative embodiment, the innersegment 12 and the outer segment 14 may be looped together at one end ofthe stent 10. For example, the mesh segments of one end of the innersegment 12 may be engaged with or locked with mesh segments of one endof the outer segment 14.

As used herein, the term “inverted end” will refer to the location wherethe outer segment 14 is folded over or looped with the inner segment 12.The inverted end 16 may form one open end of the tubular stent 10. By“inverted end” it is to be understood that the end is not limited to oneparticular embodiment wherein the stent 10 is inverted over itself.Rather, the term “inverted end” also includes embodiments incorporatingtwo separate segments 12 and 14, which may be connected or looped at the“inverted end” 16.

The open end of the stent 10 located axially opposite the inverted end16 will be referred to herein as the “distal end” 22, and may be anyshape or pattern desired. The distal end 22 may include a flared end, abarbed end, or any atraumatic end desired, or alternatively, it maysimply be an open end. For example, the distal end 22 may be formed bybending the filaments 20 at or about the middle portion of the length ofthe filaments 20 to form bends and beginning the braid at this end.Alternatively, the distal end 22 may have its wire(s) or filament(s) 20welded or looped to form an atraumatic end. Either or both of the ends16 and 22 of the stent 10 may have atraumatic ends. Thus, the stent 10as implanted is a generally cylindrical, hollow tubular structure havingtwo axially opposed open ends. In this embodiment, one open end is theinverted end 16, and the other open end is the distal end 22, which mayalso optionally have an inverted end, a flared end or a flared invertedend. The ends may be the same, or they may be different.

In an alternate embodiment, both ends of the stent 10 may include aninverted end 16, which includes the inner segment 12 and the outersegment 14, which outer segment 14 has been inverted over the innersegment 12. In this embodiment, there will be two outer segments 14,inverted over the inner segment 12. The stent 10 may be inverted onitself more than one time, for example, it may have any number ofdesired layers. More layers may help the stent 10 in overall anchoring,i.e., by preventing migration once it has been implanted.

As used herein, the term “free end” 18 refers to the end of the outersegment 14, which has been inverted over the inner segment 12. The freeend 18 of the outer segment 14 may be attached to the inner segment 12,or alternatively it may be left unattached to the inner segment 12.Attachment may be made by any means desired, including looping, weaving,adhering, suturing or other desired attachment. In another embodiment,the free end 18 of the outer segment 14 may be attached to itself toform loops. The free end 18 of the outer segment 14 may be locatedapproximately at the same location as the distal end 22 of the stent 10,or alternatively it may be located axially closer to the inverted end16. Further, in one embodiment, the free end 18 may extend axiallybeyond the distal end 22.

Referring to FIGS. 3 and 4, an embodiment in which the outer segment 14is folded over the inner segment 12 is illustrated. To demonstrate thefull effect of folding the stent 10 over itself, the outer segment 14 islabeled with the letter “B”, and the inner segment 12 is labeled withthe letter “A”. FIG. 3 depicts the stent 10 prior to folding. Theunfolded stent 10 includes the inner section 12 and the outer section14, in an axial arrangement. As can be seen, the unfolded stent 10 is alinear, tubular structure, where the free end 18 of the outer segment 14is located at one axial end of the stent 10, and the distal end 22 islocated at the opposite axial end of the stent 10. Both segments 12 and14 include a series of braided filaments 20. The braided filaments 20may be continuous throughout the stent 10 or they may be individualfilaments 20 attached or adhered to each other.

FIG. 4 illustrates the stent 10 of FIG. 3, after the outer segment 14has been folded over the inner segment 12. As can be seen, the free end18 of the outer segment 14 is now located at a location axially closerto the distal end 22 of the stent 10. The inverted end 16 now forms theopen end of the stent 10 located axially opposite the distal end 22.

In an alternate embodiment, the distal end 22 may be folded over theinner segment 12, forming a dual-folded stent. Optional double layerstent configurations include those disclosed in U.S. Pat. No. 6,264,689to Colgan et al., the contents of which are incorporated herein byreference.

Thus, the segments 12 and 14 may be formed from two distinct stentbodies, or alternately they may be formed from one continuous body.Optionally, the outer segment 14 may be formed separately and attachedto the inner segment 12. Such attachment may be by any means desired,such as by welding or other means including crimping, clipping, orsuturing. Alternatively, the segments 12 and 14 may be fittedconcentrically and left unattached. In embodiments where the outersegment 14 and the inner segment 12 are made of separate tubularstructures, the two segments 12 and 14 are preferably attached to eachother by the above means.

Optionally, the distal end 22 or may have portions which have varieddiameters, such as tapered portions, flared portions and/or flangedportions. Similarly, the free end 18 may have similar properties or itmay be different. As depicted in FIGS. 3 and 4, the distal end 22 isshown as a flared end. Alternatively, the distal end 22 may be tapered,or it may have any number of extending ends, including barbs or otherattachment means.

Desirably, the filaments 20 are made from any suitable implantablematerial, such as metals, plastics, or other materials. However, it ispreferred that the filaments 20 be constructed of a biocompatible metalor polymeric material. Such suitable materials include, withoutlimitation nitinol, stainless steel, cobalt-based alloy such asElgiloy®, platinum, gold, titanium, tantalum, niobium, polymericmaterials and combinations thereof. Useful and nonlimiting examples ofpolymeric stent materials include poly(L-lactide) (PLLA),poly(D,L-lactide) (PLA), poly(glycolide) (PGA),poly(L-lactide-co-D,L-lactide) (PLLA/PLA), polyethylene terephthalate(PET), poly(L-lactide-co-glycolide) (PLLA/PGA),poly(D,L-lactide-co-glycolide) (PLA/PGA), poly(glycolide-co-trimethylenecarbonate) (PGA/PTMC), polydioxanone (PDS), Polycaprolactone (PCL),polyhydroxybutyrate (PHBT),poly(phosphazene)poly(D,L-lactide-co-caprolactone) PLA/PCL),poly(glycolide-co-caprolactone) (PGA/PCL), poly(phosphate ester) and thelike. The filaments 20 may include materials made from or derived fromnatural sources, such as, but not limited to collagen, elastin,glycosaminoglycan, fibronectin and laminin, keratin, alginate, extracellular matrix, or combinations thereof and the like.

Filaments 20 made from polymeric materials may also include radiopaquematerials, such as metallic-based powders, particulates or pastes whichmay be incorporated into the polymeric material. For example theradiopaque material may be blended with the polymer composition fromwhich the polymeric wire is formed, and subsequently fashioned into thestent as described herein. Alternatively, the radiopaque material may beapplied to the surface of the metal or polymer stent. In eitherembodiment, various radiopaque materials and their salts and derivativesmay be used including, without limitation, bismuth, barium and its saltssuch as barium sulphate, tantulaum, tungsten, gold, platinum andtitanium, to name a few. Additional useful radiopaque materials may befound in U.S. Pat. No. 6,626,936, which is herein incorporated in itsentirely by reference. Metallic complexes useful as radiopaque materialsare also contemplated. The stent may be selectively made radiopaque atdesired areas along the wire or made be fully radiopaque, depending onthe desired end-product and application. Further, the filaments 20 mayhave an inner core of tantalum, gold, platinum, iridium or combinationof thereof and an outer member or layer of nitinol to provide acomposite wire for improved radiocapicity or visibility. Desirably, theinner core is platinum and the outer layer is nitinol. More desirably,the inner core of platinum represents about at least 10% of the wirebased on the overall cross-sectional percentage. Moreover, nitinol thathas not been treated for shape memory such as by heating, shaping andcooling the nitinol at its martensitic and austenitic phases, is alsouseful as the outer layer. Further details of such composite wires maybe found in U.S. Patent Application Publication 2002/0035396 A1, thecontents of which is incorporated herein by reference. Preferably, thefilaments 20 are made from nitinol, or a composite wire having a centralcore of platinum and an outer layer of nitinol.

The materials of the stent 10, as well as the materials forming thefilaments 20, may be further enhanced with coverings, films, coatings,and other materials. A covering, film, or coating may be in the form ofa tubular structure, or it may be placed directly onto the surface ofthe filaments 20. The coating may be a substantially continuous layer.The filaments 20 may be covered or may be left bare, or combinationsthereof. For example, portions of the stent 10 may include coveredfilaments 20, while other portions may include bare filaments 20.Further, portions of the filaments 20, such as the portion on the inner(luminal) surface of the stent 10, may be covered.

In one preferred embodiment, the filaments 20 which make up the outersegment 14 may be coated, while the filaments 20 which make up the innersegment 12 may be bare. The coating may be made of any material which issuitable for implantation into the body. Coatings may include anyplastic or polymeric material, desirably a hard but flexible plasticmaterial. Alternatively, the coating may be silicone or silicone-likematerial. Coatings may be applied to the filaments 20 prior to braidingor after the filaments 20 have been braided.

In another optional embodiment, any portion of the stent 10 may becovered with a continuous coating layer, such as a sleeve or liner 26.Alternatively, the stent 10 may be covered with a discontinuous layeracross at least a portion of the mesh segment. Such sleeves or linersmay alternatively be constructed of other biocompatible materials,including but not limited to polymeric materials, such as polyethylene,polypropylene, polyvinyl chloride, polytetrafluoroethylene, includingexpanded polytetrafluoroethylene (ePTFE), fluorinated ethylenepropylene, fluorinated ethylene propylene, polyvinyl acetate,polystyrene, poly(ethylene terephthalate), naphthalene, dicarboxylatederivatives, such as polyethylene naphthalate, polybutylene naphthalate,polytrimethylene naphthalate and trimethylenediol naphthalate,polyurethane, polyurea, silicone rubbers, polyamides, polyimides,polycarbonates, polyaldehydes, polyether ether ketone, natural rubbers,polyester copolymers, styrene-butadiene copolymers, polyethers, such asfully or partially halogenated polyethers, and copolymers andcombinations thereof. Fillers such as metals, carbon fibers, glassfibers and ceramics may be incorporated into the coatings, sleeves orliners. The liner or liners may be on the stent 10, components of thestent 10, and combinations thereof. For example, the liner may belocated on the inner surface of the stent 10, or it may be located onthe outer surface of the stent 10. The sleeve or liner 26, in part or intotal, may be temporary, for example bioabsorbable, biodegradable, andthe like, or may be permanent (i.e., not substantially bioabsorbable orbiodegradable), for example the above-described biocompatible metals,alloys, polymers and biological materials.

Stent 10 may be treated with a therapeutic agent or agents. “Therapeuticagents”, “pharmaceuticals,” “pharmaceutically active agents”, “drugs”and other related terms may be used interchangeably herein and includegenetic therapeutic agents, non-genetic therapeutic agents and cells.Therapeutic agents may be used singly or in combination. A wide varietyof therapeutic agents can be employed in conjunction with the presentinvention including those used for the treatment of a wide variety ofdiseases and conditions (i.e., the prevention of a disease or condition,the reduction or elimination of symptoms associated with a disease orcondition, or the substantial or complete elimination of a disease orcondition).

Non-limiting examples of useful therapeutic agents include, but are notlimited to, adrenergic agents, adrenocortical steroids, adrenocorticalsuppressants, alcohol deterrents, aldosterone antagonists, amino acidsand proteins, ammonia detoxicants, anabolic agents, analeptic agents,analgesic agents, androgenic agents, anesthetic agents, anorecticcompounds, anorexic agents, antagonists, anterior pituitary activatorsand suppressants, anthelmintic agents, anti-adrenergic agents,anti-allergic agents, anti-amebic agents, anti-androgen agents,anti-anemic agents, anti-anginal agents, anti-anxiety agents,anti-arthritic agents, anti-asthmatic agents, anti-atheroscleroticagents, antibacterial agents, anticholelithic agents,anticholelithogenic agents, anticholinergic agents, anticoagulants,anticoccidal agents, anticonvulsants, antidepressants, antidiabeticagents, antidiuretics, antidotes, antidyskinetics agents, anti-emeticagents, anti-epileptic agents, anti-estrogen agents, antifibrinolyticagents, antifungal agents, antiglaucoma agents, antihemophilic agents,antihemophilic Factor, antihemorrhagic agents, antihistaminic agents,antihyperlipidemic agents, antihyperlipoproteinemic agents,antihypertensives, antihypotensives, anti-infective agents,anti-inflammatory agents, antikeratinizing agents, antimicrobial agents,antimigraine agents, antimitotic agents, antimycotic agents,antineoplastic agents, anti-cancer supplementary potentiating agents,antineutropenic agents, antiobsessional agents, antiparasitic agents,antiparkinsonian drugs, antipneumocystic agents, antiproliferativeagents, antiprostatic hypertrophy drugs, antiprotozoal agents,antipruritics, antipsoriatic agents, antipsychotics, antirheumaticagents, antischistosomal agents, antiseborrheic agents, antispasmodicagents, antithrombotic agents, antitussive agents, anti-ulcerativeagents, anti-urolithic agents, antiviral agents, benign prostatichyperplasia therapy agents, blood glucose regulators, bone resorptioninhibitors, bronchodilators, carbonic anhydrase inhibitors, cardiacdepressants, cardioprotectants, cardiotonic agents, cardiovascularagents, choleretic agents, cholinergic agents, cholinergic agonists,cholinesterase deactivators, coccidiostat agents, cognition adjuvantsand cognition enhancers, depressants, diagnostic aids, diuretics,dopaminergic agents, ectoparasiticides, emetic agents, enzymeinhibitors, estrogens, fibrinolytic agents, free oxygen radicalscavengers, gastrointestinal motility agents, glucocorticoids,gonad-stimulating principles, hemostatic agents, histamine H2 receptorantagonists, hormones, hypocholesterolemic agents, hypoglycemic agents,hypolipidemic agents, hypotensive agents, HMGCoA reductase inhibitors,immunizing agents, immunomodulators, immunoregulators, immunostimulants,immunosuppressants, impotence therapy adjuncts, keratolytic agents, LHRHagonists, luteolysin agents, mucolytics, mucosal protective agents,mydriatic agents, nasal decongestants, neuroleptic agents, neuromuscularblocking agents, neuroprotective agents, NMDA antagonists, non-hormonalsterol derivatives, oxytocic agents, plasminogen activators, plateletactivating factor antagonists, platelet aggregation inhibitors,post-stroke and post-head trauma treatments, progestins, prostaglandins,prostate growth inhibitors, prothyrotropin agents, psychotropic agents,radioactive agents, repartitioning agents, scabicides, sclerosingagents, sedatives, sedative-hypnotic agents, selective adenosine A1antagonists, adenosine A2 receptor antagonists (e.g., CGS 21680,regadenoson, UK 432097 or GW 328267), serotonin antagonists, serotonininhibitors, serotonin receptor antagonists, steroids, stimulants,thyroid hormones, thyroid inhibitors, thyromimetic agents,tranquilizers, unstable angina agents, uricosuric agents,vasoconstrictors, vasodilators, vulnerary agents, wound healing agents,xanthine oxidase inhibitors, and the like, and combinations thereof

Useful non-genetic therapeutic agents for use in connection with thepresent invention include, but are not limited to:

-   -   (a) anti-thrombotic agents such as heparin, heparin derivatives,        urokinase, clopidogrel, and PPack (dextrophenylalanine proline        arginine chloromethylketone);    -   (b) anti-inflammatory agents such as dexamethasone,        prednisolone, corticosterone, budesonide, estrogen,        sulfasalazine and mesalamine;    -   (c) antineoplastic/antiproliferative/anti-miotic agents such as        paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,        epothilones, endostatin, angiostatin, angiopeptin, monoclonal        antibodies capable of blocking smooth muscle cell proliferation,        and thymidine kinase inhibitors;    -   (d) anesthetic agents such as lidocaine, bupivacaine and        ropivacaine; [0048]    -   (e) anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone,        an RGD peptide-containing compound, heparin, hirudin,        antithrombin compounds, platelet receptor antagonists,        anti-thrombin antibodies, anti-platelet receptor antibodies,        aspirin, prostaglandin inhibitors, platelet inhibitors and tick        antiplatelet peptides;    -   (f) vascular cell growth promoters such as growth factors,        transcriptional activators, and translational promotors;    -   (g) vascular cell growth inhibitors such as growth factor        inhibitors, growth factor receptor antagonists, transcriptional        repressors, translational repressors, replication inhibitors,        inhibitory antibodies, antibodies directed against growth        factors, bifunctional molecules consisting of a growth factor        and a cytotoxin, bifunctional molecules consisting of an        antibody and a cytotoxin;    -   (h) protein kinase and tyrosine kinase inhibitors (e.g.,        tyrphostins, genistein, quinoxalines);    -   (i) prostacyclin analogs;    -   (j) cholesterol-lowering agents;    -   (k) angiopoietins;    -   (l) antimicrobial agents such as triclosan, cephalosporins,        aminoglycosides and nitrofurantoin;    -   (m) cytotoxic agents, cytostatic agents and cell proliferation        affectors;    -   (n) vasodilating agents;    -   (o) agents that interfere with endogenous vasoactive mechanisms;    -   (p) inhibitors of leukocyte recruitment, such as monoclonal        antibodies;    -   (q) cytokines;    -   (r) hormones;    -   (s) inhibitors of HSP 90 protein (i.e., Heat Shock Protein,        which is a molecular chaperone or housekeeping protein and is        needed for the stability and function of other client        proteins/signal transduction proteins responsible for growth and        survival of cells) including geldanamycin;    -   (t) smooth muscle relaxants such as alpha receptor antagonists        (e.g., doxazosin, tamsulosin, terazosin, prazosin and        alfuzosin), calcium channel blockers (e.g., verapimil,        diltiazem, nifedipine, nicardipine, nimodipine and bepridil),        beta receptor agonists (e.g., dobutamine and salmeterol), beta        receptor antagonists (e.g., atenolol, metaprolol and        butoxamine), angiotensin-II receptor antagonists (e.g.,        losartan, valsartan, irbesartan, candesartan, eprosartan and        telmisartan), and antispasmodic/anticholinergic drugs (e.g.,        oxybutynin chloride, flavoxate, tolterodine, hyoscyamine        sulfate, diclomine);    -   (u) bARKct inhibitors;    -   (v) phospholamban inhibitors;    -   (w) Serca 2 gene/protein;    -   (x) immune response modifiers including aminoquizolines, for        instance, imidazoquinolines such as resiquimod and imiquimod;    -   (y) human apolioproteins (e.g., AI, AII, AIII, AIV, AV, etc.);    -   (z) selective estrogen receptor modulators (SERMs) such as        raloxifene, lasofoxifene, arzoxifene, miproxifene, ospemifene,        PKS 3741, MF 101 and SR 16234;    -   (aa) PPAR agonists, including PPAR-alpha, gamma and delta        agonists, such as rosiglitazone, pioglitazone, netoglitazone,        fenofibrate, bexaotene, metaglidasen, rivoglitazone and        tesaglitazar;    -   (bb) prostaglandin E agonists, including PGE2 agonists, such as        alprostadil or ONO 8815Ly;    -   (cc) thrombin receptor activating peptide (TRAP);    -   (dd) vasopeptidase inhibitors including benazepril, fosinopril,        lisinopril, quinapril, ramipril, imidapril, delapril, moexipril        and spirapril;    -   (ee) thymosin beta 4;    -   (ff) phospholipids including phosphorylcholine,        phosphatidylinositol and phosphatidylcholine; and    -   (gg) VLA-4 antagonists and VCAM-1 antagonists.

The non-genetic therapeutic agents may be used individually or incombination, including in combination with any of the agents describedherein.

Further examples of non-genetic therapeutic agents, not necessarilyexclusive of those listed above, include taxanes such as paclitaxel(including particulate forms thereof, for instance, protein-boundpaclitaxel particles such as albumin-bound paclitaxel nanoparticles,e.g., ABRAXANE), sirolimus, everolimus, tacrolimus, zotarolimus, Epo D,dexamethasone, estradiol, halofuginone, cilostazole, geldanamycin,alagebrium chloride (ALT-711), ABT-578 (Abbott Laboratories), trapidil,liprostin, Actinomcin D, Resten-NG, Ap-17, abciximab, clopidogrel,Ridogrel, beta-blockers, bARKct inhibitors, phospholamban inhibitors,Serca 2 gene/protein, imiquimod, human apolioproteins (e.g., AI-AV),growth factors (e.g., VEGF-2), as well derivatives of the forgoing,among others.

Useful genetic therapeutic agents for use in connection with the presentinvention include, but are not limited to, anti-sense DNA and RNA aswell as DNA coding for the various proteins (as well as the proteinsthemselves), such as (a) anti-sense RNA; (b) tRNA or rRNA to replacedefective or deficient endogenous molecules; (c) angiogenic and otherfactors including growth factors such as acidic and basic fibroblastgrowth factors, vascular endothelial growth factor, endothelialmitogenic growth factors, epidermal growth factor, transforming growthfactor α and β, platelet-derived endothelial growth factor,platelet-derived growth factor, tumor necrosis factor α, hepatocytegrowth factor and insulin-like growth factor; (d) cell cycle inhibitorsincluding CD inhibitors, and (e) thymidine kinase (“TK”) and otheragents useful for interfering with cell proliferation. DNA encoding forthe family of bone morphogenic proteins (“BMP's”) are also useful andinclude, but not limited to, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1),BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14,BMP-15, and BMP-16. Currently desirably BMP's are any of BMP-2, BMP-3,BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided ashomodimers, heterodimers, or combinations thereof, alone or togetherwith other molecules. Alternatively, or in addition, molecules capableof inducing an upstream or downstream effect of a BMP can be provided.Such molecules include any of the “hedgehog” proteins, or the DNA'sencoding them.

Vectors for delivery of genetic therapeutic agents include, but notlimited to, viral vectors such as adenoviruses, gutted adenoviruses,adeno-associated virus, retroviruses, alpha virus (Semliki Forest,Sindbis, etc.), lentiviruses, herpes simplex virus, replicationcompetent viruses (e.g., ONYX-015) and hybrid vectors; and non-viralvectors such as artificial chromosomes and mini-chromosomes, plasmid DNAvectors (e.g., pCOR), cationic polymers (e.g., polyethyleneimine,polyethyleneimine (PEI)), graft copolymers (e.g., polyether-PEI andpolyethylene oxide-PEI), neutral polymers such as polyvinylpyrrolidone(PVP), SP1017 (SUPRATEK), lipids such as cationic lipids, liposomes,lipoplexes, nanoparticles, or microparticles, with and without targetingsequences such as the protein transduction domain (PTD).

Cells for use in connection with the present invention may include cellsof human origin (autologous or allogeneic), including whole bone marrow,bone marrow derived mono-nuclear cells, progenitor cells (e.g.,endothelial progenitor cells), stem cells (e.g., mesenchymal,hematopoietic, neuronal), pluripotent stem cells, fibroblasts,myoblasts, satellite cells, pericytes, cardiomyocytes, skeletal myocytesor macrophage, or from an animal, bacterial or fungal source(xenogeneic), which can be genetically engineered, if desired, todeliver proteins of interest.

Numerous therapeutic agents, not necessarily exclusive of those listedabove, have been identified as candidates for vascular treatmentregimens, for example, as agents targeting restenosis (antirestenotics).Such agents are useful for the practice of the present invention andinclude one or more of the following:

-   -   (a) Ca-channel blockers including benzothiazapines such as        diltiazem and clentiazem, dihydropyridines such as nifedipine,        amlodipine and nicardapine, and phenylalkylamines such as        verapamil;    -   (b) serotonin pathway modulators including: 5-HT antagonists        such as ketanserin and naftidrofuryl, as well as 5-HT uptake        inhibitors such as fluoxetine;    -   (c) cyclic nucleotide pathway agents including phosphodiesterase        inhibitors such as cilostazole and dipyridamole,        adenylate/Guanylate cyclase stimulants such as forskolin, as        well as adenosine analogs;    -   (d) catecholamine modulators including α-antagonists such as        prazosin and bunazosine, β-antagonists such as propranolol and        α/β-antagonists such as labetalol and carvedilol;    -   (e) endothelin receptor antagonists such as bosentan,        sitaxsentan sodium, atrasentan, endonentan;    -   (f) nitric oxide donors/releasing molecules including organic        nitrates/nitrites such as nitroglycerin, isosorbide dinitrate        and amyl nitrite, inorganic nitroso compounds such as sodium        nitroprusside, sydnonimines such as molsidomine and linsidomine,        nonoates such as diazenium diolates and NO adducts of        alkanediamines, S-nitroso compounds including low molecular        weight compounds (e.g., S-nitroso derivatives of captopril,        glutathione and N-acetyl penicillamine) and high molecular        weight compounds (e.g., S-nitroso derivatives of proteins,        peptides, oligosaccharides, polysaccharides, synthetic        polymers/oligomers and natural polymers/oligomers), as well as        C-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds        and L-arginine;    -   (g) Angiotensin Converting Enzyme (ACE) inhibitors such as        cilazapril, fosinopril and enalapril;    -   (h) ATII-receptor antagonists such as saralasin and losartin;    -   (i) platelet adhesion inhibitors such as albumin and        polyethylene oxide;    -   (j) platelet aggregation inhibitors including cilostazole,        aspirin and thienopyridine (ticlopidine, clopidogrel) and GP        IIb/IIIa inhibitors such as abciximab, epitifibatide and        tirofiban;    -   (k) coagulation pathway modulators including heparinoids such as        heparin, low molecular weight heparin, dextran sulfate and        β-cyclodextrin tetradecasulfate, thrombin inhibitors such as        hirudin, hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone)        and argatroban, FXa inhibitors such as antistatin and TAP (tick        anticoagulant peptide), Vitamin K inhibitors such as warfarin,        as well as activated protein C;    -   (l) cyclooxygenase pathway inhibitors such as aspirin,        ibuprofen, flurbiprofen, indomethacin and sulfinpyrazone;    -   (m) natural and synthetic corticosteroids such as dexamethasone,        prednisolone, methprednisolone and hydrocortisone;    -   (n) lipoxygenase pathway inhibitors such as nordihydroguairetic        acid and caffeic acid;    -   (o) leukotriene receptor antagonists;    -   (p) antagonists of E- and P-selectins;    -   (q) inhibitors of VCAM-1 and ICAM-1 interactions;    -   (r) prostaglandins and analogs thereof including prostaglandins        such as PGE1 and PG12 and prostacyclin analogs such as        ciprostene, epoprostenol, carbacyclin, iloprost and beraprost;    -   (s) macrophage activation preventers including bisphosphonates;    -   (t) HMG-CoA reductase inhibitors such as lovastatin,        pravastatin, atorvastatin, fluvastatin, simvastatin and        cerivastatin;

(u) fish oils and omega-3-fatty acids;

-   -   (v) free-radical scavengers/antioxidants such as probucol,        vitamins C and E, ebselen, trans-retinoic acid, SOD (orgotein)        and SOD mimics, verteporfin, rostaporfin, AGI 1067, and M 40419;    -   (w) agents affecting various growth factors including FGF        pathway agents such as bFGF antibodies and chimeric fusion        proteins, PDGF receptor antagonists such as trapidil, IGF        pathway agents including somatostatin analogs such as        angiopeptin and ocreotide, TGF-β pathway agents such as        polyanionic agents (heparin, fucoidin), decorin, and TGF-β        antibodies, EGF pathway agents such as EGF antibodies, receptor        antagonists and chimeric fusion proteins, TNF-α pathway agents        such as thalidomide and analogs thereof, Thromboxane A2 (TXA2)        pathway modulators such as sulotroban, vapiprost, dazoxiben and        ridogrel, as well as protein tyrosine kinase inhibitors such as        tyrphostin, genistein and quinoxaline derivatives;    -   (x) matrix metalloprotease (MMP) pathway inhibitors such as        marimastat, ilomastat, metastat, batimastat, pentosan        polysulfate, rebimastat, incyclinide, apratastat, PG 116800, RO        1130830 or ABT 518;    -   (y) cell motility inhibitors such as cytochalasin B;    -   (z) antiproliferative/antineoplastic agents including        antimetabolites such as purine antagonists/analogs (e.g.,        6-mercaptopurine and pro-drugs of 6-mercaptopurine such as        azathioprine or cladribine, which is a chlorinated purine        nucleoside analog), pyrimidine analogs (e.g., cytarabine and        5-fluorouracil) and methotrexate, nitrogen mustards, alkyl        sulfonates, ethylenimines, antibiotics (e.g., daunorubicin,        doxorubicin), nitrosoureas, cisplatin, agents affecting        microtubule dynamics (e.g., vinblastine, vincristine,        colchicine, Epo D, paclitaxel and epothilone), caspase        activators, proteasome inhibitors, angiogenesis inhibitors        (e.g., endostatin, angiostatin and squalamine), olimus family        drugs (e.g., sirolimus, everolimus, tacrolimus, zotarolimus,        etc.), cerivastatin, flavopiridol and suramin;    -   (aa) matrix deposition/organization pathway inhibitors such as        halofuginone or other quinazolinone derivatives, pirfenidone and        tranilast;    -   (bb) endothelialization facilitators such as VEGF and RGD        peptide;    -   (cc) blood rheology modulators such as pentoxifylline and    -   (dd) glucose cross-link breakers such as alagebrium chloride        (ALT-711).

These therapeutic agents may be used individually or in combination,including in combination with any of the agents described herein.

Numerous additional therapeutic agents useful for the practice of thepresent invention are also disclosed in U.S. Pat. No. 5,733,925 to Kunz,the contents of which are incorporated herein by reference.

A wide range of therapeutic agent loadings may used in connection withthe dosage forms of the present invention, with the pharmaceuticallyeffective amount being readily determined by those of ordinary skill inthe art and ultimately depending, for example, upon the condition to betreated, the nature of the therapeutic agent itself, the tissue intowhich the dosage form is introduced, and so forth.

In some embodiments, a coating or a sleeve or liner 26 may be disposedon the inner surface of the stent 10, the outer surface of the stent 10,or combinations thereof. For example, as can be seen in FIGS. 3 and 4,the inner portion 12 may include a liner 26 on its inner surface, whilethe outer portion 14 may not include a liner 26. The incorporation of aliner 26 on the inner surface of the inner segment 12 allows for asmoother flow of fluid or materials through the stent 10, whereas theunlayered outer segment 14 is pressed against the inner surface of alumen. In this design, the outer segment 14, being unlayered, wouldanchor better to the lumen wall, because it has been left unlayered,while the inner segment 12 would prevent or reduce tissue ingrowthbecause it is layered.

The stent 10 alternatively may be embedded, partially or entirely, inthe coating sleeve or liner 26. For example, the wires or filaments 20may be dip-coated in a polymer such as silicone or other polymer.

Further, in some embodiments, only certain regions of the stent 10, suchas a flared or tapered distal end 22, may be covered with a liner 26. Inaddition, the liner 26 may be a tubular sleeve, which may be disposed onthe inner or outer surface of the stent 10. Other similar variations andplacements of a liner 26 at other locations on the stent 10 arecontemplated. Each end may have a different layer than the other, oreach may have the same layer.

Methods of introducing and implanting the stent 10 of the presentinvention are provided herein. Any known implantation methods aresuitable for the placement of the stent 10 of the present invention. Forexample, the stent may be implanted through the use of any knowndelivery device. The stent 10 is typically inserted through the use of acatheter while the stent 10 is in a collapsed state. In one preferredembodiment, the stent 10 is a self-expanding stent. The stent 10 may beinserted into the inner surface of any bodily lumen, including, forexample, the esophageal or an arterial lumen. Once inserted, the stent10 self-expands, and pushes the wall of the lumen outward, enlarging theregion of the lumen in which it is implanted. For example, theimplantation site may be at least partially blocked with a tumorousgrowth, making the passage of bodily fluids or other desired materialstherethrough difficult, if not impossible. The stent 10 may be implantedat the site of the growth, and allowed to expand. Expansion opens theblocked lumen, allowing for the passage of fluids or materialstherethrough.

As discussed previously, the stent 10 of the present invention may be adual-layered structure, incorporating two concentrically disposed meshsegments 12 and 14. The stent 10 may, for example, include an innersegment 12 including at least one inner wire, and an outer segment 14including at least one outer wire. If desired, the outer segment 14 mayform a continuous connection with the inner segment 12. The innersegment 12 and the outer segment 14 may be in contact with each other,or they may be spaced apart. Each of the segments 12 and 14 exert anoutward force on the lumen, which increases the ability of the stent 10to resist migration through the lumen. Further, in one embodiment, theouter segment 14 is coated with a material as described above, such assilicone, which may assist in frictional engagement to the inner surfaceof the lumen. Such coating further aids in the resistance to migration.In other embodiments, the outer segment 14 may include barbs or othercomponents which serve to increase the adherence to the inner surface ofthe lumen. Thus, the stent 10, after implantation, is adhered to theinner surface of the lumen, and is sufficiently placed so as to resistmigration through the lumen. As set forth above, the inner segment 12and the outer segment 14 may be any desired configuration, including,for example, braided, knitted, twisted, and the like.

In one embodiment of the invention, incorporating the stent wherein theouter segment 14 is inverted over the inner segment 12, aids in theadjustment, removal and/or replacement of the stent 10 afterimplantation, while still maintaining the high adherence andanti-migration capabilities. The use of the continuous, dual-layeredstent 10 in this embodiment allows for the operator to easily remove orreplace the stent 10 even after implantation. After implantation, theinner segment 12 may be pulled toward the distal end 22, which serves toconstrict the connected outer segment 14, and results in peeling thestent 10 away from the inner surface of the lumen. Since the innersegment 12 is not adhered directly to the lumen, or is at least not astightly frictionally engaged to the lumen as the dual-layered portion,removal and replacement of the stent 10 is much easier for the operatorto accomplish. This is especially true if the inner and outer segments12 and 14 have different constructs, as peeling may be made easier. Theinterface area may be made compliant to effectuate removal.

Further, after implantation, the inner segment 12 may be moved in eitherdirection along the axis of the tubular stent 10 (i.e., towards thedistal end 22 or towards the inverted end 16), which results in eitherincreasing or decreasing the length of the outer segment 14, respectiveto the inner segment 12. For example, should the operator wish todecrease the length of the outer segment 14, the operator may pull theinner segment 12 towards the distal end 22 of the stent 10. Pulling theinner segment 12 towards the distal end 22 of the stent 10 results in aportion of the outer segment 14 being constricted and pulled towards theinner segment 12, reducing the length of the outer segment 14. Likewise,the operator may push the inner segment 12 towards the inverted end 16of the stent 10, which results in the portion of the inner segment 12being folded back, becoming part of the outer segment 14 of the stent10. This resizing may take place at one or both ends. Further, theresizing may be accomplished at any time, including days or weeks afterimplantation as needed. The ability to increase or decrease the axiallength of the dual-layered stent 10 in vivo gives the operator a greatdeal of latitude during implantation.

It may be desired to implant a tubular stent, where the implantedtubular stent is formed of at least two stents joined thereto. In suchembodiments, the user may first implant a stent, there the stentincludes a first stent body having a generally cylindrical mesh segment.The first stent body is preferably formed of at least one first wire,the first wire forming a plurality of intersecting crossing points todefine an open lattice tubular wall as described above. The user maythen implant a second stent, where the second stent includes a secondstent body having a generally cylindrical mesh segment. As with thefirst stent, the second stent body is preferably formed of at least onesecond wire, the second wire forming a plurality of intersectingcrossing points to define an open lattice tubular wall. The user maythen at least partially connect an end of the first stent body to an endof the second stent body so as to form a multi-layered stent.

While various embodiments of the present invention are specificallyillustrated and/or described herein, it will be appreciated thatmodifications and variations of the present invention may be affected bythose skilled in the art without departing from the spirit and intendedscope of the invention. Further, any of the embodiments or aspects ofthe invention as described in the claims or throughout the specificationmay be used with one and another without limitation.

1. A tubular stent comprising: a. an inner section comprising at leastone first wire, the inner section defined by intersecting crossingpoints of the at least one first wire; and b. a concentric outer sectioncomprising at least one second wire, the outer section defined byintersecting crossing points of the at least one second wire; whereinthe inner section does not form a continuous connection with the outersection, and wherein the concentric outer section is folded over theinner section.
 2. The stent of claim 1, wherein the inner section isattached to the outer section.
 3. The stent of claim 1, furthercomprising at least one flared end.
 4. The stent of claim 3, wherein theconcentric outer section is folded back over the inner section at an endopposite the flared end.
 5. The stent of claim 1, wherein the first andsecond wires are braided.
 6. The stent of claim 1, wherein the inner andouter sections comprise 8 to 24 wires.
 7. The stent of claim 1, furthercomprising a coating provided on at least one of the inner section orouter section.
 8. The stent of claim 7, wherein the coating comprises anactive agent.
 9. The stent of claim 8, wherein the coating comprises asubstantially continuous layer.
 10. The stent of claim 1, furthercomprising at least one additional concentrically disposed section.